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Ann Allergy Asthma Immunol. Author manuscript; available in PMC 2017 April 01.
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Published in final edited form as:

Ann Allergy Asthma Immunol. 2016 April ; 116(4): 306–312.e1. doi:10.1016/j.anai.2015.12.025.

Pre- and postnatal stress and wheeze in Mexican children: Sex-

specific Differences
Maria José Rosa, DrPH1, Allan C. Just, PhD1, Marcela Tamayo y Ortiz, ScD2, Lourdes
Schnaas, PhD3, Katherine Svensson, MS1, Robert O. Wright, MD, MPH1,5, Martha María
Téllez Rojo, PhD2, and Rosalind J. Wright, MD, MPH4,5
Maria José Rosa: maria.rosa@mssm.edu; Allan C. Just: allan.just@mssm.edu; Marcela Tamayo y Ortiz:
mtamayo@hsph.harvard.edu; Lourdes Schnaas: lschnaas@hotmail.com; Katherine Svensson:
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katherine.svensson@mssm.edu; Robert O. Wright: robert.wright@mssm.edu; Martha María Téllez Rojo:

mmtellez@insp.mx; Rosalind J. Wright: rosalind.wright@mssm.edu
1Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
2National Institute of Public Health, Cuernavaca, Mexico
3National Institute of Perinatology, Mexico DF, Mexico
4Kravis
Children’s Hospital, Department of Pediatrics, Icahn School of Medicine at Mount Sinai,
New York, NY, United States
5Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New
York, NY, United States
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Keywords
negative life events; perinatal stress; postnatal stress; childhood wheeze; sex- and temporal-
specific effects

Introduction
Childhood wheezing is an important contributor to morbidity and health care utilization in
Latin America.1, 2 The study of environmental risk factors for the development of childhood
wheezing and asthma in Latin America is a growing area of interest.3, 4 Identifying critical
exposure windows for prevalent risk factors can provide insight into the mechanisms
through which these exposures lead to respiratory disease in childhood and ultimately
inform the timing of public health interventions.
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Corresponding Author: Rosalind J. Wright, MD, MPH, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA.
Telephone: +1 (212) 241-5287; Fax: +1 (212) 289-8569; rosalind.wright@mssm.edu.
Authors’contributions: MJR generated data, performed analyses, interpreted data and drafted the manuscript. ACJ, MTO, LS and KS
generated data, assisted in analysis and interpretation of data and revised the manuscript. ROW, MMTR and RJW conceived and
designed original study, assisted in analysis and interpretation of the data and manuscript preparation and revisions.
Conflicts of interest: None
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 Rosa et al. Page 2

Although asthma and childhood wheeze are heterogeneous conditions, inflammation is a

central pathological feature.5 Psychosocial stress leads to the activation of systems involved
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in the regulation of inflammatory processes (i.e., hypothalamic-pituitary-adrenocortical

[HPA] axis, autonomic nervous system) and alterations in innate and adaptive immune
responses.6 Hormones and neuropeptides released after the activation of stress response
systems are involved in inflammatory7 and airway responses8 so the study of psychosocial
stressors as environmental risk factors for respiratory disease might be particularly relevant.

A growing number of prospective epidemiological studies demonstrate associations between

increased prenatal maternal stress or stress correlates (e.g., maternal anxiety) and early
asthma phenotypes.9–13 In Boston, children whose mothers reported higher numbers of
negative life events during both the prenatal and early postnatal period were three times
more likely to have recurrent wheeze by age 2 years when compared to mothers with low
stress during both periods.9 An inner-city cohort study in New York City reported
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associations between prenatal maternal demoralization, a broad measure of maternal

psychological functioning, and increased risk of transient and persistent wheeze in
children.12 Another multi-site U.S. inner-city cohort study reported associations between
prenatal perceived stress and wheeze in one year old infants. 14 Maternal pregnancy-specific
hassles were associated with a composite measure of respiratory illnesses during infancy.15
In a study in the Netherlands, maternal distress assessed using the Brief Symptom Inventory
during pregnancy was associated with increased odds of wheezing in children followed to
age 6 years; maternal distress examined postnatally was not associated with child wheeze.13
A recent study linked higher intra-familial adverse childhood experiences with increased
odds of asthma diagnosis in children in the National Survey of Children’s Health.16
Overlapping evidence suggests that exposure to stress may be an important contributing
factor to respiratory morbidity in Latin America due to high prevalence of intimate partner
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violence17, local violence18, perinatal depression19 and lack of data on stress-reduction

strategies.4 Despite growing evidence in this area, similar studies in Latin American
countries are lacking.

Growing evidence from animal models demonstrate that the timing of stress exposure
(prenatal vs. postnatal) is important and that critical windows of vulnerability may differ by
sex of the offspring for a number of developmental outcomes.20, 21 For example, one study
found that male offspring of dams exposed to stress early in the prenatal period showed
maladaptive behavioral stress responsivity in a series of tests.22 In another study, females
exhibited increased anxiety-related behavior after exposure to prenatal stress while males
showed decreased memory for novel objects and novel spatial locations.23 Although
mechanisms have not been fully elucidated, studies suggest that sex-specific effects can arise
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through differential placental effects and fetal sex hormones.24, 25 For example, one recent
study looking at prenatal socioeconomic adversity and epigenetic changes in placenta, found
sex-differences in methylation of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), the
enzyme responsible for the conversion of cortisol into inactive cortisone, suggesting that
prenatal environmental cues may affect fetal programming to respond to stress postnatally in
a sex-specific manner.26

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Epidemiological studies considering sex-specific effects of perinatal stress on childhood

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respiratory disorders are sparse and have yielded mixed results. In a large study using
electronic records in Sweden, boys born to women who experienced bereavement, defined as
the loss of a close family member during the second trimester, were found to have higher
risk of asthma.27 Another small study looking at subjective distress experienced during
pregnancy due to the 1998 Quebec ice storm found that only girls had higher odds of
lifetime wheezing, doctor diagnosis of asthma and asthma medication use by age 12 years.28
However, these studies were limited by their inability to examine prenatal and postnatal
stress concurrently and adjust for other important confounders.

We examined whether higher maternal stress, assessed in pregnancy and postnatally, was
associated with increased likelihood of wheeze in children enrolled in a Mexico City
pregnancy cohort followed to age 4 years. Specifically, we first examined effects of pre- and
postnatal stress in separate models, next we mutually adjusted for pre-/postnatal stress, and
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finally we examined joint effects of exposure to increased stress in both pregnancy and the
first two years of life. We also examined whether temporal effects of perinatal stress differed
relative to the child’s sex.

Methods
Study population
The Programming Research in Obesity, Growth, Environment and Social Stressors
(PROGRESS) recruited women pregnant women who were receiving health insurance and
prenatal care through the Mexican Social Security System (Instituto Mexicano del Seguro
Social –IMSS) between July 2007 and February 2011. The IMSS provides healthcare to
affiliated private sector employees, the majority low- to middle-income workers and their
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families. Women were eligible to participate in the study if they met the following criteria:
less than 20 weeks gestation, greater than 18 years of age, planned to stay in Mexico City for
the next 3 years, had access to a telephone, had no medical history of heart or kidney
disease, did not consume alcohol daily, and did not use any steroid or anti-epilepsy
medications. Following birth, 815 mother-child dyads had at least one follow-up visit and
417 had all the necessary covariates for these analyses. There were no significant differences
between participants who had all necessary covariates when compared to those who did not
by mother’s age at delivery, maternal asthma, child’s sex or prenatal ETS exposure (eTable
1, online supplement). Procedures were approved by institutional review boards at the
Harvard School of Public Health, Icahn School of Medicine at Mount Sinai, and the
Mexican National Institute of Public Health. Women provided written informed consent.
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Measures of psychosocial stress

The Crisis in Family Systems-Revised (CRISYS) survey, which has been validated in
Spanish29, was administered by a trained psychologist during the second or third trimester of
pregnancy and during the 48-month visit. The CRISYS questionnaire assesses life events
across 11 domains: financial, legal, career, relationship, home safety, neighborhood safety,
medical issues (self and others), home, prejudice and authority. Participants rated life events
occurring in the past 6 months as positive, negative or neutral. Previous research has shown

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increased vulnerability across multiple domains, therefore domains with one or more
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negative life event were summed into a negative life event (NLE) domain score, with higher
scores indicating greater stress.9, 30

Outcome measures
The validated Spanish version of the International Study of Asthma and Allergies in
Childhood (ISAAC) questionnaire was administered starting at the 48-month visit. Ever
wheeze was determined based on caregiver report of “Has your child ever had wheezing or
whistling in the chest at any time in the past?” and current wheeze was defined based on
response to “Has your child had wheezing or whistling of the chest in the past 12 months?”

Covariates
Child’s sex, mother’s age at delivery and mother’s report of ever having asthma were
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collected through questionnaires. Exposure to environmental tobacco smoke was ascertained

during pregnancy (either during the second or third trimester) and during the 48-month visit
through report of any smoker in the home during these time periods. Exposure to particulate
matter 2.5 microns and less in diameter (PM2.5) was estimated for each women during
pregnancy and over the first postnatal year using a novel spatio-temporal model
incorporating Moderate Resolution Imaging Spectroradiometer (MODIS) satellite-derived
Aerosol Optical Depth (AOD) measurements at a 1× 1 km spatial resolution.31 These remote
sensing data are calibrated with municipal ground level monitors of PM2.5, land use and
meteorological data to yield estimates of daily residential PM2.5 levels for each study
participant. Daily PM2.5 exposure was averaged for the entire gestational period (estimated
date of conception to delivery date) and over the first year postpartum.
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Statistical Analyses
First, prenatal and postnatal negative life domain (NLE) scores were analyzed in separate
models. Associations were explored by modeling NLE scores as continuous measures using
generalized additive models (GAMs). In order to obtain risk ratios for our prospectively
measured dichotomous outcomes, data were analyzed using a modified Poisson regression
approach.32 Models were adjusted for child’s sex, report of any smoker in the home during
pregnancy, report of any smoker in the home at 48 months, mother’s age at delivery,
maternal ever asthma, and average PM2.5 exposure during pregnancy and one year postnatal.
Socioeconomic status (SES) was also examined as a potential confounder, but was not
independently associated with the outcome not did it significantly affect the estimate and
was excluded from final analyses. Potential sex-differences were examined by including an
interaction term for sex by NLE score in each model and by stratifying by sex. Interactions
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between prenatal and postnatal stress were also explored in the entire cohort and in models
stratified by sex.

Results
Table 1 shows the distribution of covariates over the entire sample and stratified by child
sex. The range of prenatal and postnatal NLE domain scores was 0-11 and 0-9, respectively;
25% of children had ever wheeze and 12% current wheeze. Sample characteristics did not

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significantly differ by sex with the exception of wheeze outcomes which were both more
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frequent among boys (p<0.05, Table 1). As seen in table 2, pre- and postnatal NLE scores
(spearman ρ=0.45, p<0.001) and average PM2.5 concentrations during pregnancy and one
year postnatal (spearman ρ=0.31, p<0.001) were moderately correlated. NLE domain scores
and PM2.5 concentrations were not significantly correlated.

In fully adjusted models, there was a significant association between each unit increase in
prenatal stress and risk of ever wheeze (RR: 1.08, 95%CI [1.00, 1.16]) and wheeze in the
past 12 months (RR: 1.12, 95%CI [1.00, 1.26]). Increasing postnatal stress was also
significantly associated with an increase in risk of ever wheeze (RR: 1.12, 95%CI [1.04,
1.21]) and wheeze in the past 12 months (RR: 1.21, 95%CI [1.08, 1.35]). Figures 1 and 2
depict the relationship between NLE domain scores for each period and wheeze outcomes
for the overall sample and stratified by child sex. In the overall sample, the most
parsimonious fit from the smooth GAM function was a linear association of increasing risk
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with number of reported negative life event domains for both ever and current wheeze
outcomes. In sex-stratified models, boys seemed more impacted by increasing prenatal stress
while girls seemed more impacted by higher postnatal stress in relation to ever wheeze
(Figure 1). In Figure 2, associations seemed more similar in boys and girls although the
relationship between increasing postnatal stress and current wheeze was steeper among girls
compared to boys. Table 3 shows the results for interaction models between sex and pre- and
postnatal stress. The interaction term was only significant for sex*postnatal stress in relation
to current wheeze. Furthermore, after stratifying by sex, postnatal stress was associated with
increased risk of current wheeze only in girls (p=0.04). We also explored a potential
interaction between higher stress in both the pre- and postnatal periods in relation to wheeze
outcomes. In adjusted models, interaction terms were not significant in our overall sample or
in the sex-stratified models (all p-values >0.2).
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Discussion
This is the first study to prospectively examine associations between pre- and postnatal
stress and wheeze outcomes in an urban pediatric population in Mexico. In general, we saw
an exposure-response relationship between stress in these early life periods and wheeze
outcomes in these Mexican children. Our findings of an exposure-response relationship
between maternal negative life events in the perinatal period and early childhood asthma
phenotypes are consistent with another study the U.S.9 In addition, there was a suggestion
that prenatal stress was more strongly associated with wheeze outcomes in boys compared to
girls while higher postnatal stress had a stronger association among girls. Indeed we found a
significant interaction between increased postnatal stress and child sex in relation to current
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wheeze with the association of stress being greater in girls. The observed associations
remained significant after adjustment for a number of important confounders.

Stress during pregnancy may disrupt maternal systems like the HPA axis, the sympathetic-
adrenal-medullary system and immunomodulation. This disruption may lead to a
potentiation of the fetal immune system through the upregulation of maternal and
fetoplacental cytokine or IgE production.33, 34 We have previously shown that prenatal stress
is associated with disruption in maternal-fetal HPA-axis functioning indexed by altered

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cortisol production35 and subsequently linked stress-related alterations in cortisol production

during pregnancy with higher odds of repeated wheeze during infancy.36 Prenatal stress may
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also influence autonomic nervous system functioning, fetal programming of brain

neurotransmitter systems, and the HPA axis which alters the child’s neural regulation of
immune function.37, 38

Children remain vulnerable to stress postnatally as the stress response systems remain highly
reactive and labile in response to environmental stressors.39, 40 For example, exposure to
maternal stress during infancy and childhood has been associated with altered HPA axis
functioning in children.41 There is evidence from animal models that impaired
glucocorticoid function resulting from stress is associated with corticosteroid insensitivity.42
In a murine model, mice exposed to repeat social stress postnatally had prolonged airway
inflammation after allergen challenge, activation of both innate and adaptive immune
systems, and diminished endogenous corticosteroid response.43 In addition, psychosocial
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stress might alter mothers’ health behaviors perinatally and may contribute to other factors
linked to childhood wheeze like maternal smoking.44 Notably adjustment for any smoking in
the home, both pre- and postnatally, did not change our findings.

In our study, the association between postnatal maternal stress and current wheeze was
higher in girls than in boys whereas there was a suggestion that boys were more vulnerable
prenatally in relationship to ever wheeze. These findings are consistent with research
showing that the vulnerable window in which stress has the greatest influence may differ
based on offspring sex and the outcome being considered. Even though these mechanisms
have not been fully elucidated, differential effects of prenatal stress on developmental
outcomes may be due to sex-specific placental responsiveness to prenatal maternal stress and
fetal sex hormones.45, 46 Male fetuses may be more sensitive to stress in utero due to
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reduced activity and/or sensitivity of placental 11β-hydroxysteroid dehydrogenase type 2

(11β-HSD2), leading to increased fetal glucocorticoid exposure, differential DNA
methylation in the placenta,26 or enhanced vulnerability to stress-induced oxidation in
utero.47 The interactions between sex hormones and immune-inflammatory pathways may
cause females to be more vulnerable to the effects of prenatal stress on certain inflammatory
disorders.25 Conversely, females may also be relatively protected from the effects of prenatal
stress due to sex-specific differences in the relationship between fetal and placental
glucorticoid response.26 Exposure to prenatal stress may lead to altered programming of the
stress response and individuals exposed to stress prenatally may be more vulnerable to
subsequent stressful events due to these alterations (ie “two-hit model”).48 Moreover, studies
show that a poor postnatal environment can modulate the consequences of in utero exposure
to stress in a sex-specific manner, with females generally being more adversely affected.49
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This should be further explored in future research.

Strengths of our study include the prospective design, assessment of stress in pregnancy and
in the first two years of life (i.e., previously identified vulnerable developmental windows
for asthma risk and stress programming) using a well-validated measure of negative life
events, focus on an understudied population in Mexico City with respect to stress and
children’s respiratory health, and our ability to adjust for important confounders including
PM2.5 exposure during pregnancy and the first year of life.50 We also acknowledge some

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limitations. Prenatal stress was assessed based on maternal report of negative events
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occurring in the past 6 months and while most women answered the CRISYS in the 3rd
trimester (92%), some variability in timing of assessment may result in measurement error.
This measurement error would be expected to be similar in women regardless of whether
their child goes on to develop wheeze (i.e., nondifferential misclassification) resulting in an
underestimation of the association between stress and asthma. Children’s wheeze was
reported by mothers; however, caregiver-reported wheeze is commonly used in moderate- to
larger-sized epidemiological studies51, 52 and this was assessed using a standardized
measure validated for Spanish-speaking populations.52 This analysis did not include a
measure of the biological stress response, even if the participants perceived an even as
negative this might not lead to a negative response due to that event. There is some evidence
that positive life event exposure is associated with reduced cortisol levels in pregnant
women53 and may have a protective function.54, 55 We calculated a positive life event score
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(summing those items women endorsed as positive) for both the prenatal and 48 month
period and this score was not a significant predictor of ever or current wheeze. Future studies
should aim to include measures of stress response (e.g., stress hormones, autonomic
reactivity, etc.), examine more definitive outcomes including physician diagnosed asthma or
lung function as these children continue to be followed. It is also possible that women
experiencing higher stress might underreport their child’s symptoms, due to being
overwhelmed or not aware of the child but this would lead to an underestimation of the true
relationship. Conversely, women experiencing higher stress might overreport symptoms if
they are more attentive to their children’s health.56 Mothers in the study were not aware of
the hypothesis linking stress to wheeze in their children. Also, it is reassuring that other
variables in the model (maternal asthma, sex) were associated with wheeze in the same
direction reported by previous studies.57, 58
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Our prospective study adds to a growing literature underscoring the need to consider
psychosocial stress as an important programming factor for wheezing respiratory illnesses in
early life and is first to examine these associations in a Latin American sample. Knowledge
of risk factors and sex-differences in early development and insight into critical windows of
exposure can inform prevention and intervention strategies that may preclude persistence of
symptoms or lung function deficits in later childhood. Significant sex biases in the natural
history, pathophysiology, and response to treatment in respiratory disorders such as asthma
are not well understood.59, 60 Studies examining the programming of sex differences at
varying developmental time points in response to maternal and early life stress may provide
unique insights into asthma etiology and natural history. Future interventions should
consider stress reduction modalities in pregnant women and the early postpartum period.
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Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
Funding: The (PROGRESS) project has been funded by grants R01 ES021357 (Wright RO, PI). Phenotyping and
biostatistical support was funded by P30 ES023515. During preparation of this manuscript, RJW was supported by
and R01HL095606; MJR was supported by T32 HD049311-09. This study was supported and partially funded by

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the National Institute of Public Health/Ministry of Health of Mexico and we thank the ABC (American British
Cowdray) Hospital in Mexico for providing research facilities.
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Abbreviations

CRISYS Crisis in Family Systems-Revised questionnaire

HPA hypothalamic-pituitary-adrenocortical
ISAAC International Study of Asthma and Allergies in Childhood
NLE Negative Life Events
PM2.5 Particulate matter <2.5 microns in diameter

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Figure 1. Exposure-response relationship between prenatal and postnatal NLE domain scores
and ever wheeze a) overall, b) in boys and c) in girls
For overall results, generalized additive models (GAM) were adjusted for child’s sex,
maternal asthma, maternal age at delivery, average PM2.5 during pregnancy, average PM2.5
postnatal year one, report of a smoker in the home prenatally and at 48 months. Stratified
models adjusted for maternal age at delivery, average PM2.5 during pregnancy, average
PM2.5 postnatal year one, report of a smoker in the home prenatally and at 48 months.
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Figure 2. Exposure-response relationship between prenatal and postnatal NLE domain scores
and current wheeze a) overall, b) in boys and c) in girls
For overall results, generalized additive models (GAM) were adjusted for child’s sex,
maternal asthma, maternal age at delivery, average PM2.5 during pregnancy, average PM2.5
postnatal year one, report of a smoker in the home prenatally and at 48 months. Stratified
models adjusted for maternal age at delivery, average PM2.5 during pregnancy, average
PM2.5 postnatal year one, report of a smoker in the home prenatally and at 48 months.
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Table 1

Sample characteristics
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Characteristic Overall n=417 Boys n=211 Girls n=206 p-valuea

Maternal asthma, n (%) 7 (1.7) 6 (2.8) 1 (0.5) 0.12

Prenatal ETS* exposure, n (%) 160 (38.4) 78 (37) 82 (39.8) 0.55

Postnatal ETS exposure, n (%) 53 (13) 24 (11.4) 29 (14.1) 0.41

Mother’s age at delivery, median (25th–75th) 28 (24–32) 27 (23–31) 27 (23–31) 0.30

Average prenatal PM2.5 μg/m3, median (25th–75th) 23 (21–24) 23 (21–24) 23 (20–24) 0.23

Average PM2.5 μg/m one year postnatal, median (25th–75th) 23 (20–24) 23 (20–24) 23 (20–24) 0.53

Prenatal NLE domain score, median, (range) 3 (0–11) 3 (0–11) 3 (0–10) 0.93
Postnatal NLE domain score, median, (range) 3 (0–9) 3 (0–8) 3 (0–9) 0.51
Ever wheeze, n (%) 107 (26) 63 (29.9) 44 (21.4) 0.05
Current wheeze, n (%) 55 (13) 36 (17.1) 19 (9.2) 0.02
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a
Differences in categorical variables tested using Fisher’s Exact test and Pearson Chi-Square test. Differences in continuous variables tested using
Mann Whitney U test.
*
ETS: Environmental tobacco smoke
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Table 2

Spearman correlations between prenatal and postnatal stress and ambient air pollution concentrations

Prenatal NLE score Postnatal NLE score Prenatal PM2.5 concentration

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ρ P ρ P ρ P
Postnatal NLE score 0.45 <0.001
Prenatal PM2.5 concentration −0.01 0.77 −0.01 0.77

Postnatal year 1 PM2.5 concentration 0.02 0.64 0.06 0.18 0.31 <0.001

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Table 3

Sex-stratified associations between maternal stress and wheeze outcomes

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NLE Domain Score Boys N=211 Girls N=206 p-value for interaction
Ever wheeze
Prenatal 1.12 (1.02, 1.24) 1.03 (0.92, 1.15) 0.25
Postnatal 1.09 (0.99, 1.20) 1.16 (1.03, 1.30) 0.48
Current wheeze
Prenatal 1.11 (0.96, 1.28) 1.11 (0.93, 1.34) 0.81
Postnatal 1.11 (0.97, 1.27) 1.35 (1.13, 1.61) 0.04

Overall models adjusted for child’s sex, maternal asthma, maternal age at delivery, average PM2.5 during pregnancy, average PM2.5 postnatal year
one, report of a smoker in the home prenatally and at 48 months. Stratified models adjusted for maternal age at delivery, average PM2.5 during
pregnancy, average PM2.5 postnatal year one, and report of a smoker in the home prenatally and at 48 months.
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